Zofenopril calcium of formula (I), chemically named (4S)-1-[(2S)-3-(benzoylthio)-2-methylpropionyl]-4-(phenylthio)-L-proline calcium salt, is a non-peptidic orally active sulphydryl ACE inhibitor with a long-lasting action and it is currently marketed for the treatment of hypertension.

The manufacturing process for many pharmaceuticals is hindered by the fact that the organic compound which is the active ingredient has handling difficulties during the manufacturing process and may impart undesirable properties to the final drug or dosage form. In addition it can be difficult to control the polymorphic form of the active pharmaceutical ingredient throughout the manufacturing process.
For pharmaceuticals in which the active ingredient can exist in more than one polymorphic form, it is particularly important to ensure that the manufacturing process for the active ingredient affords a single polymorph with a consistent level of polymorphic purity. If the process leads to a polymorph with varying degrees of polymorphic purity and/or where the process does not control polymorphic interconversion, serious problems in dissolution and/or bioavailability can result in the finished pharmaceutical composition comprising the active ingredient.
Zofenopril calcium polymorphs are disclosed in patents U.S. Pat. Nos. 6,515,012 and 4,316,906. The method for the preparation of zofenopril calcium as disclosed in U.S. Pat. No. 4,316,906 is described in U.S. Pat. No. 6,515,012 as comprising steps as follows:    (a) condensation between cis-4-(phenylthio)-L-proline and (D)-3-(benzoylthio)-2-methylpropionyl chloride in aqueous solution keeping the pH at values of 8-8.5 by addition of 5N sodium hydroxide, subsequent acidification with HCl, extraction with isobutyl acetate and concentration of the extracts, washing with saline solution, to give (4S)-1-[(2S)-3-(benzoylthio)-2-methylpropinoyl]-4-(phenylthio)-L-proline;    (b) treatment of the resinous material from the previous step in isopropanol solution with potassium 2-ethyl-hexanoate to obtain the corresponding potassium salt;    (c) dissolution of the potassium salt in water to a 57% concentration and very slow addition, with simultaneous seeding, of a slight excess of a 2N calcium chloride aqueous solution to precipitate the desired calcium salt, washing the resulting product thoroughly with water, drying under vacuum at a comparatively high temperature to give the desired calcium salt as dry powder with a melting point of about 250° C.;    (d) alternatively, (4S)-1-[(2S)-3-(benzoylthio)-2-methylpropinoyl]-4-(phenylthio)-L-proline is dissolved in ethanol and treated with the same volume of an aqueous suspension containing one equivalent of CaO; after removing ethanol and subsequently washing with ether, the aqueous suspension is freeze-dried to obtain the calcium salt with a melting point of 235-237° C.
According to U.S. Pat. No. 6,515,012, the synthesis described in U.S. Pat. No. 4,316,906 (cited above at points a, b and c) mainly yields polymorph form A, but also polymorph form B in very variable percentages and never below 20%. Moreover, the alternative synthesis described (cited at point d) affords a partially amorphous product with very variable characteristics in which form A, when present, is in concentrations much lower than those obtained in the preceding process.
U.S. Pat. Nos. 6,515,012 and 6,521,760 disclose a process for the preparation of substantially pure polymorph form A from zofenopril calcium, comprising the following steps:    (a) reaction of S(−)-3-(benzoylthio)-2-methyl-propanoic acid chloride and cis-4-(phenylthio)-L-proline in water at a pH ranging from 9.0-9.5 and recovery of zofenopril in its acidic form;    (b) salification of acid zofenopril with a potassium salt in alcoholic solution and recovery of the resulting potassium salt;    (c) conversion of the potassium salt to the calcium salt by addition of an aqueous solution of zofenopril potassium salt to a calcium chloride aqueous solution at 70-90° C. with simultaneous seeding to promote the precipitation of polymorph form A.
However, the synthesis disclosed in the aforesaid US patents for the preparation of polymorph form A has the disadvantage that the reaction is carried out at a relatively high temperature (80-85° C.) at which interconversion of the polymorphs is possible. Consequently, although substantially pure form A can be obtained from the above process, it is not very reliable and the possibility of traces of form B cannot be completely eliminated.
The aforesaid US patents also disclose a process for the preparation of polymorph form B, comprising the following steps:    (a) A solution of zofenopril potassium salt (0.27M) is sprayed in lukewarm water (55° C.), while adding a calcium chloride solution, the solution being such that the total amount of drug and calcium chloride are equimolar.    (b) The resulting suspension containing the slurry product is heated at 85° C. for 12-14 hours to obtain complete conversion to form B.    (c) After cooling at about 25° C., the product is filtered, washed with water until it is substantially free from chloride ions, and then dried under vacuum.
WO 2007/003963 discloses a process for the preparation of substantially pure polymorph form C (monohydrate form) of zofenopril calcium, comprising the following steps:    (a) reaction of S(−)-3-(benzoylthio)-2-methyl-propanoic acid chloride and cis-4-(phenylthio)-L-proline in water at a pH ranging from 9.0-9.5 and recovery of zofenopril in its acidic form;    (b) salification of acid zofenopril with a potassium salt in alcoholic solution and recovery of the resulting potassium salt;    (c) conversion of the potassium salt to the calcium salt by addition of an aqueous solution of calcium chloride dihydrate to an aqueous solution of zofenopril potassium salt at 50-55° C.
The polymorph form C described in the aforesaid WO 2007/003963 patent application has the advantage that it is prepared at milder conditions than the experimental conditions reported for the polymorphs A and B. In addition, it was found to be purer with respect to contamination by other forms (polymorph forms A and B) as indicated by XRPD data, and generally more stable to polymorphic interconversion.
However, although the properties of form C and the processes to prepare it are generally better and more convenient that those described for previous polymorphic forms, it has been observed that under certain conditions during dosage form preparation, such as micronization or wet granulation, the form C product can exhibit very slight changes in polymorphic purity. Although this difference was only to a very small extent, it could lead to variation in dissolution profile and subsequent problems in the pharmaceutical composition development.
Although formulation development may be able to circumvent the potential problems with form C, it was considered that an alternative polymorphic form with improved properties over all the known polymorphic forms may make development and manufacture more convenient and efficient and could also lead to improved pharmaceutical compositions.